RGMc (Repulsive Guidance Molecule c), or hemojuvelin, has been genetically linked with the iron overloading disorder juvenile hemochromatosis. Patients with juvenile hemochromatosis and RGMc knockout mice exhibit iron overloading in the liver, heart, and pancreas, and have decreased hepatic expression of the key iron regulatory protein, hepcidin. These observations suggest that RGMc plays a critical role in the regulation of systemic iron homeostasis, although its mechanisms of action are unknown. Initial studies have shown that RGMc binds to the transmembrane protein neogenin. The focus of this application is to test the hypothesis that neogenin functions as a receptor for RGMc. The following Specific Aims are proposed to test this hypothesis: 1. to define the nature of the interaction between RGMc and neogenin, 2; to determine whether neogenin mediates the biological actions of RGMc. [unreadable] [unreadable] [unreadable]